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ToxSci Advance Access originally published online on May 16, 2007
Toxicological Sciences 2007 98(2):375-394; doi:10.1093/toxsci/kfm122
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Polychlorinated Biphenyls–Modulated Tumorigenesis in Sprague–Dawley Rats: Correlation with Mixed Function Oxidase Activities and Superoxide (O2•–) Formation Potentials and Implied Mode of Action

John F. Brown, Jr*,{dagger},1, Brian A. Mayes{dagger}, Jay B. Silkworth{dagger} and Stephen B. Hamilton*

* General Electric Company, Fairfield, Connecticut 06431 {dagger} General Electric Company, Global Research Center, One Research Circle, Niskayuna, New York 12309

1 To whom the correspondence should be addressed at 1479 Dean St., Niskayuna, NY 12309-5235. Fax: (518) 862-2702. E-mail john.brown{at}ge.com.

Received December 19, 2006; accepted May 8, 2007


  Abstract

Parallel, chronic (24 months) multidose bioassays of the PCB (polychlorinated biphenyls) Aroclors 1016, 1242, 1254, and 1260 in male and female Sprague–Dawley rats showed sex/Aroclor-dependent increases in hepatic tumors and decreases in extrahepatic tumors. To elucidate the PCB mode of action (MOA) involved, levels of a number of hypothesized mediators were measured in liver specimens collected at 3, 6, 12, 18, and 24 months and screened for correlation with late life hepatotumorigenesis (HT; mostly adenomas). Consistently correlated with HT were (1) tissue accumulations of {Sigma}PCBs (correlated in both sexes) and of dioxin equivalents (toxic equivalency [TEQ]; correlated in females only); (2) net activities of six groups of mixed function oxidases (MFOs), some PCB-induced, some PCB-repressed, as determined by differential metabolism of PCB congeners; (3) activities of deproteinated, reoxidized hepatic cytosols as catalysts for superoxide (O2•–) production, such activity having the chemical characteristics of redox-cycling quinones (RCQs), e.g., those derived from the glutathionylated estrogen catechols that were identified in the female rat livers; and (4) increased expression of the indicator of cell proliferation, proliferating cell nuclear antigen. The new findings, along with other recently reported relationships, were indicative of a MOA consisting of (1) {Sigma}PCB/TEQ accumulation in rat tissues; (2) {Sigma}PCB/TEQ repression of constitutive MFOs; (3) {Sigma}PCB/TEQ induction of other MFOs; (4) MFO-mediated formation of RCQs; (5) RCQ-mediated formation of O2•–; (6) O2•– dismutation to H2O2; and (7) H2O2-mediated mitotic signaling, resulting in the proliferation of spontaneously or otherwise initiated cells to form hepatic tumors, as in tumor promotion.

Key Words: Tumorigenesis; cancer; rat; PCB; PH50; quinone; RO3; superoxide.


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